Purpose: The purpose of the present study is to determine the safety and tolerability and potential clinical efficacy of subcutaneous doses of recombinant human IL-4 (rHuIL-4) in patients with rheumatoid arthritis (RA). RA is a chronic inflammatory disease of unknown etiology. It is characterized by synovial inflammation with frequent progression to articular cartilage and bone destruction. The synovial inflammatory response in RA consists predominately of T lymphocytes, mostly T helper cells (Th), with fewer numbers of macrophages and B lymphocytes. The Th cells can be divided into two overlapping subpopulations with important functional significance, Th1 and Th2 cells. Th1 cells secrete IL-2 and interferon- and regulate cell-mediated responses. Th2 cells secrete IL-4, IL-5, and IL-10, and mediate humoral responses. Most Th cells in the rheumatoid joint belong to the Th1 subpopulation. The synovial tissue in RA exhibits other features typical of a cell-mediated response, including hypervascularity, upregulation of cell adhesion molecules, and overexpression of pro-inflammatory cytokines such as IL-1 and tumor necrosis factor (TNF)- . IL-4, a cytokine produced by Th2 cells and macrophages, has primarily immunosuppressive and anti-inflammatory properties. The inhibitory effects of IL-4 have been observed in animal models of arthritis where it can ameliorate joint inflammation. Methods: The study is a multicenter, double-blind, placebo-controlled, escalating dose (0.5, 1.0, and 2.0 5g/kg) clinical trial with a dosing period of 6 weeks. The main outcomes for the study are the frequency and severity of adverse effects and the American College of Rheumatology Core Disease Measures. Results: The study has been completed. A total of four patients were enrolled at this site. The study population was predominantly female (3/1) and Caucasian. The study drug was well tolerated and did not cause any serious adverse event reactions. One patient, a Caucasian male, was seen during the reporting period. There were two serious adverse events that occurred during the course of the study. One patient with a past history of supraventricular tachycardia, hypertension, and hypothyroidism (managed with Levothyroxin) was admitted to the hospital for atrial fibrillation. Because of the cardiotoxicity profile of IL-4 in preclinical trials, the investigator considers the atrial fibrillation to be possibly related to the study drug. The second serious adverse event concerned a patient who was admitted for hip replacement surgery. This patient had long- standing disease and a past history of multiple joint replacements. IL-4 treatment did not improve disease measures. Significance: RA is widely believed to be a Th1-mediated disease, although the data to support this hypothesis is circumstantial. For example, Th1 cells are associated with cellular immune responses, which seems to fit with the characteristics of rheumatoid joint inflammation, and T cell clones isolated from synovial tissue of RA patients most often secrete Th1 cytokines. Additional insights into whether RA is a Th-driven response in RA may be obtained by examining the treatment and biological effects of cytokines that downregulate Th1 responses. Future plans: Since, interleukin-4 did not yield the expected effect in RA patients, there are no plans for future studies at this time.